Carbocyclizations 6,7-bicyclic systems

When the cnolate of an enone is brought into reaction with an enone, usually a carbocyclic system is prepared by two consecutive Michael additions (M1MIRC reactions). Due to the lower temperatures employed and the absence of diene polymerization these reactions are useful alternatives for Diels-Alder reactions and proceed in general with high diastereoselectivities. When neither enolate nor enone is cyclic a monocyclic system is formed 338 which can be converted into a bicyclic system when the Michael addition is followed by an aldol reaction339. When, however, the enolate is cyclic a bicyclic or a tricyclic system is formed340 341. 

Feringa and co-workers described the tandem addition-aldol cyclization protocol leading to the formation of 6,6-, 6,7-, and 6,8-annulated bicyclic systems (Scheme 68).39 Using Cu(n)-29 as catalyst and functionalized organozinc reagents as nucleophiles, the conjugate addition reaction followed by aldol cyclization can offer highly enantioselec-tive annulation products (up to 98% ee). This method can be used in the synthesis of carbocyclic compounds, such as steroids, terpenes, and other natural products. 

Recent advances in the rhodium-catalyzed [4-1-2] reactions have led to the development of the first highly regioselective intermolecular cyclization, providing access to new classes of carbocycles with both activated and unactivated substrates. The chemo- and stereoselective carbocyclizations of tethered diene-allene derivatives afford new classes of 5,6- and 6,6-bicyclic systems. Additionally, examination of a wide range of factors that influence both diastereo- and enantioselectivity has provided a significant advance in the understanding of catalyst requirements across these systems. 

Bi- and tricyclic carbocyclic ring systems can be easily obtained from (1-alkynyl)carbene complexes in two or more reaction steps without isolation of intermediate products. For example, the bicyclic 1,3-dienone 44 has been generated from compound le in a two-step cycloaddition/annulation procedure involving [4+2] cycloaddition of a diene to the C=C bond of a (l-alkynyl)carbene complex and a subsequent Dotz reaction.68 Furthermore, a 1,4-dioxy dihydronaphthalene 45 was obtained from the silyl derivative lg in a similar reaction sequence. In contrast to the methyl derivative 44, the corresponding silyl derivative generated from lg undergoes facile... 

The regiospecific 5-exo-trig cyclizations of substituted 5-hexenyllithiums was exploited for the stereoselective synthesis of bicyclic systems by tandem cyclization of acyclic diolefinic alkyllithiums [42]. However, this carbocycle synthesis has three major limitations ... 

A review has appeared covering the chemistry of carbocyclic nucleosides published over the period 1994-1998, discussing compounds with ring sizes from three to six, and also bicyclic systems. ... 

In view of screening the structural and functional properties of deox-yoligonucleotides incorporating 3, 5 -bicyclic 2-deoxy nucleosidic building blocks, Leumann developed a synthetic sequence to prepare the thymine-based phosphoramidite (11) in which the bicyclic system incorporates a 5-membered ring ribose adjacent to a six-membered carbocyclic ring. In this isomer, the cyclohexyl ring adopted a chair conformation with the 5 -substituent in an axial position while the furanoside moiety adopted a... 

Ghosh and co-workers used olefin metathesis as a key step in their synthesis of the carbocyclic core of e /-bacillariolide II, an oxylipin. Oxylipins are densely fiinctionalized naturally occurring bicyclic systems... 

Olefin metathesis was also used as a key step in Wicha and coworkers synthesis of the carbocyclic core of several di- and sesqui-terterpenes. Reaction of 277 with 5 mol % of 4 in refluxing benzene gave the corresponding bicyclic system 278 in 60% overall yield. 

Synthesis of Five-Membered Carbocycles. 1-Substituted al-lenylsilanes react with Q ,/3-unsaturated carbonyl compounds in the presence of titanium tetrachloride to produce cyclopentenes. For example, carvone and 1-methyl-l-(trimethylsilyl)allene react smoothly to give a ds-fused bicyclic system (eq 7). ... 

Since diazaquinones are among the most powerful dienophiles, they undergo [4+2] cycloaddition (Diels-Alder) reactions with a great variety of dienes to give various heterocyclic systems accessible with difficulty by other methods. Diazaquinone reacts with butadiene and substituted butadienes, carbocyclic and heterocyclic dienes, 1-vinylcycloalkenes, polyaromatic compounds and vinylaromatic compounds to afford bicyclic and polycyclic bridgehead diaza systems, including diazasteroids (Scheme 56). 

The following syntheses of five-membered carbocyclic systems involve radical-induced epoxide fragmentation with radical translocation and cyclization. The resulting bicyclic alcohols are formed as a mixture of two epimeric esters with cw-fused rings.[71]... 

Intramolecular cycloadditions are among the most efficient methods for the synthesis of fused bicyclic ring systems [30]. From this perspective, the hetisine skeleton encompasses two key retro-cycloaddition key elements. (1) a bridging pyrrolidine ring accessible via a [3+2] azomethine dipolar cycloaddition and (2) a [2.2.2] bicyclo-octane accessible via a [4+2] Diels-Alder carbocyclic cycloaddition (Chart 1.4). While intramolecular [4+2] Diels—Alder cycloadditions to form [2.2.2] bicycle-octane systems have extensive precedence [3+2], azomethine dipolar cycloadditions to form highly fused aza systems are rare [31-33]. The staging of these two operations in sequence is critical to a unified synthetic plan. As the proposed [3+2] dipolar cycloaddition is expected to be the more challenging of the two transformations, it should be conducted in an early phase in the forward synthetic direction. As a result, a retrosynthetic analysis would entail initial consideration of the [4+2] cycloaddition to arrive at the optimal retrosynthetic C-C bond disconnections for this transformation. 

Syntheses of Carbocyclic Compounds (1.V.2.V )-2 (.V )-Amino(4-metho-xyphenyl)methyl]cyclopropan-l-ol 392 (Scheme 1.45) has been prepared by a stepwise procedure involving a 1,3-dipolar nitrile oxide cycloaddition to allyl alcohol followed by a constmction of the cyclopropa d isoxazole system, and reduction of the bicycle (436). 

Based on a similar approach, Backvall403 established the stereochemical course of such reactions and developed efficient routes to bicyclo[4.3.0]-nonadiene and bicyclo[5.3.0]-decadiene systems. Backvall404 has also reported a Pd(02CCF3)2-catalyzed oxidative carbocyclization of allenenes (Scheme 125). The process is efficient even with catalyst loading as low as 1 mol%, although if requires/>-benzoquinone as the stoichiometric oxidant, which represents the first example of a C-C bond formation using a catalytic amount of Pd(ll). Bicyclic adducts have been obtained in... 

The bicyclic 3,4-dihydropyridines (51) and (53) illustrate that the electrocyclic ring opening is sensitive to substituents (80TL599). The 3,4-dihydropyridine (51) has been observed to be in equilibrium with the azepine (50). Consistent with the analogous carbocyclic system, norcaradiene-cycloheptatriene, the monocycle (50) is the predominant species present in this equilibrium. In contrast, the dimethyl derivatives (52) and (53) exist almost exclusively in the 3,4-dihydropyridine form. A greater steric interaction between these methyl substituents in (52) was given in explanation of these observations. 

Homo-l//-azepines (29), unlike their carbocyclic counterparts, show little tendency to isomerize to the thermodynamically less favoured bicyclic aziridine tautomers (30). Presumably, the homoazepine gains its stability from delocalization of the nitrogen lone pair through the dienamine system <71AG(E)ll). However, the aziridine tautomers (30 R1 = C02Me, R2 = Ac, C02Me or p-Ts) have been trapped as their all-cTs bis-l,3-dipolar cycloadducts with diazomethane (76CB3505). 

The crucial structural feature which underlies the aromatic character of benzenoid compounds is of course the cyclic delocalised system of six n-electrons. Other carbocyclic systems similarly possessing this aromatic sextet of electrons include, for example, the ion C5Hf formed from cyclopentadiene under basic conditions. The cyclopentadienide anion is centrosymmetrical and strongly resonance stabilised, and is usually represented as in (7). The analogous cycloheptatrienylium (tropylium) cation (8), with an aromatic sextet delocalised over a symmetrical seven-membered ring, is also demonstrably aromatic in character. The stable, condensed, bicyclic hydrocarbon azulene (Ci0H8) possesses marked aromatic character it is usually represented by the covalent structure (9). The fact that the molecule has a finite dipole moment, however, suggests that the ionic form (10) [a combination of (7) and (8)] must contribute to the overall hybrid structure. 

Cycloaddition to a-P-unsaturated carbonyl systems represented by different carbohydrate enones yield annulated osides. These bicyclic molecules are used for synthesis of carbocyclic systems using the stereochemical information issued from sugar... 

The next four procedures describe the regioselective preparation of bicyclic ring systems, specifically, condensed five-membered carbocyclic derivatives. A large... 

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